TY - JOUR
T1 - Endothelial epas1 deficiency is sufficient to promote parietal epithelial cell activation and fsgs in experimental hypertension
AU - Luque, Yosu
AU - Lenoir, Olivia
AU - Bonnin, Philippe
AU - Hardy, Lise
AU - Chipont, Anna
AU - Placier, Sandrine
AU - Vandermeersch, Sophie
AU - Xu-Dubois, Yi Chun
AU - Robin, Blaise
AU - Lazareth, Héléne
AU - Souyri, Michéle
AU - Guyonnet, Léa
AU - Baudrie, Véronique
AU - Camerer, Eric
AU - Rondeau, Eric
AU - Mesnard, Laurent
AU - Tharaux, Pierre Louis
N1 - Funding Information:
This study was supported by Institut National de la Santé et de la Recherche Médicale, the “VASCULOPHAGY” grant from the Fondation de France, the “SWITCHES” project of the Agence Nationale de la Recherche, and the European Research Council (ERC; grant 107037) to P.-L.T. Y.L. is a recipient of Fonds d’Etudes et de Recherche du Corps Médical (Assistance Publique des Hôpitaux de Paris, Paris, France), Société Française de Bienfaisance et d’Enseignement de San Sebastian-Donostia (Spain), and Société de Néphrologie grants. O.L. held postdoctoral fellowships from Société Francophone de Diabète and the Institut de France “Lefoulon-Delalande fellowship.”
PY - 2017/12
Y1 - 2017/12
N2 - FSGS, the most common primary glomerular disorder causing ESRD, is a complex disease that is only partially understood. Progressive sclerosis is a hallmark of FSGS, and genetic tracing studies have shown that parietal epithelial cells participate in the formation of sclerotic lesions. The loss of podocytes triggers a focal activation of parietal epithelial cells, which subsequently formcellular adhesions with the capillary tuft. However, in the absence of intrinsic podocyte alterations, the origin of the pathogenic signal that triggers parietal epithelial cell recruitment remains elusive. In this study, investigation of the roleof the endothelial PASdomain-containingprotein 1 (EPAS1), a regulatorya subunit of the hypoxia-inducible factor complex, during angiotensin II-induced hypertensive nephropathy provided novel insights intoFSGSpathogenesis in the absenceof a primarypodocyte abnormality.We infused angiotensin II into endothelial-selective Epas1 knockout mice and their littermate controls. Although the groups presented with identical high BP, endothelial-specific Epas1 gene deletion accentuated albuminuria with severe podocytelesions andrecruitment of pathogenic parietalglomerularepithelial cells.These lesions anddysfunctionof the glomerular filtration barrier were associated with FSGS in endothelial Epas1-deficient mice only. These results indicate that endothelial EPAS1 has a global protective role during glomerular hypertensive injuries without influencing the hypertensive effect of angiotensin II. Furthermore, these findings provide proof of principle that endothelial-derived signaling can trigger FSGS and illustrate the potential importance of the EPAS1 endothelial transcription factor in secondary FSGS.
AB - FSGS, the most common primary glomerular disorder causing ESRD, is a complex disease that is only partially understood. Progressive sclerosis is a hallmark of FSGS, and genetic tracing studies have shown that parietal epithelial cells participate in the formation of sclerotic lesions. The loss of podocytes triggers a focal activation of parietal epithelial cells, which subsequently formcellular adhesions with the capillary tuft. However, in the absence of intrinsic podocyte alterations, the origin of the pathogenic signal that triggers parietal epithelial cell recruitment remains elusive. In this study, investigation of the roleof the endothelial PASdomain-containingprotein 1 (EPAS1), a regulatorya subunit of the hypoxia-inducible factor complex, during angiotensin II-induced hypertensive nephropathy provided novel insights intoFSGSpathogenesis in the absenceof a primarypodocyte abnormality.We infused angiotensin II into endothelial-selective Epas1 knockout mice and their littermate controls. Although the groups presented with identical high BP, endothelial-specific Epas1 gene deletion accentuated albuminuria with severe podocytelesions andrecruitment of pathogenic parietalglomerularepithelial cells.These lesions anddysfunctionof the glomerular filtration barrier were associated with FSGS in endothelial Epas1-deficient mice only. These results indicate that endothelial EPAS1 has a global protective role during glomerular hypertensive injuries without influencing the hypertensive effect of angiotensin II. Furthermore, these findings provide proof of principle that endothelial-derived signaling can trigger FSGS and illustrate the potential importance of the EPAS1 endothelial transcription factor in secondary FSGS.
UR - http://www.scopus.com/inward/record.url?scp=85031730014&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/28928136
U2 - 10.1681/ASN.2016090960
DO - 10.1681/ASN.2016090960
M3 - Article
C2 - 28928136
AN - SCOPUS:85031730014
SN - 1046-6673
VL - 28
SP - 3563
EP - 3578
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -